Recombinant Human Hyaluronidase Pretreatment of CSII Cannula

Recombinant Human Hyaluronidase Pretreatment of CSII Cannula Sites Provides Comparable
Glycemic Control with Reduced Hypoglycemia in T1DM Compared to Usual CSII
85-LB
IRL B HIRSCH1, BRUCE W BODE2, JAY S SKYLER3, SATISH K GARG4, JOHN B BUSE5, DANIEL E VAUGHN6, XIONGHUA W WU6, SIMON R BRUCE6, DOUGLAS B MUCHMORE6
Recombinant human hyaluronidase (rHuPH20) is FDA-approved to increase
dispersion and absorption of injected drugs. In CSII, a single pretreatment
of the cannula site with rHuPH20 accelerates exposure and action of bolus
doses of rapid analogs for up to 3 days of catheter use. 456 subjects with
T1DM (age 48±13 years, BMI 28.5±5.1, screening A1C 7.8±0.7) were
randomized 3:1 to rapid acting analog (RAI) CSII with rHuPH20
pretreatment or usual RAI CSII for 6 months. A1C fell 0.14% from baseline
7.69% with rHuPH20 and 0.18% from baseline 7.70% for CSII alone. The
primary endpoint of A1C noninferiority (0.4% margin) was achieved with a
treatment difference of 0.05% (95% CI -0.08 to 0.18) with similar % of
subjects reaching A1C <7.0% (20.9% with rHuPH20 and 17.5% for CSII
alone, p=.45). Mean overall 90 min post-meal glucose excursion was 18.8
mg/dL with rHuPH20 and 19.7 for CSII alone (p=.79). There were fewer
hypoglycemic events (HEs) with rHuPH20 than for CSII alone. The protocol
specified primary HE analysis was based on event rates after a month of
active titration following randomization. Documented HEs ≤70 mg/dL
(obtained from SMBG uploads of >261,000 records) were reduced 12%
from 13.8/subject-month for standard CSII vs 12.1 with rHuPH20 (p=.076),
while documented HEs <56 mg/dL were reduced 23% from 4.0/mo to 3.1
(p=0.021). Nocturnal HEs (≤70 mg/dL between 23:00 and 06:00 hrs) were
reduced 21% (p=.023). Severe HEs occurred at a rate of 0.188 per subjectyear for standard CSII and 0.073 with rHuPH20 (61% reduction, p=.080) .
Adverse event rates were generally comparable between treatments,
although rHuPH20 pretreatment was associated with an increased
incidence of infusion site pain (typically mild transient burning) from 6.2%
to 14.9%. We conclude that pretreatment of CSII cannulas with rHuPH20 is
well tolerated and results in similar glycemic control in T1DM with
reduction of hypoglycemia.
The rationale for a more
physiologic insulin absorption
profile
• There is consensus that further optimization of
insulin absorption profiles, including timing and
consistency, could facilitate meeting glycemic
treatment targets without increasing rates of
hypoglycemia.1
• Faster absorption of insulin and a more
physiologic timing profile could enable
technology such as closed-loop artificial
pancreas models.
• Hylenex® recombinant (human hyaluronidase
injection; rHuPH20) is FDA-indicated to increase
dispersion and absorption of other injected
drugs2
• rHuPH20 rapidly, reversibly, and locally
depolymerizes hyaluronan in the subcutaneous
space to increase dispersion and absorption of
injected drugs and leading to an “ultrafast,” more
physiologic insulin profile.3,4
• “Fast-In” insulin profile can lead to less
postprandial hyperglycemia while “Fast-Out”
insulin profile can improve late postprandial
hypoglycemia risk.5
Study Design, Methods and Subjects
1º Endpoint : A1C Noninferiority Achieved
(Upper CI = 0.18, Prespecified Margin = 0.4)
Primary Objective
• Compare the 6 month metabolic outcome (i.e. A1C) and safety of Hylenex
recombinant preadministration in CSII to standard CSII treatment (A1C
difference from baseline to endpoint, local tolerability, immunogenicity,
adverse events and hypo- and hyperglycemia rates)
Hylenex Pretreatment
(N=296)
Bolus Timing (before vs. after meals) Influences both
Postprandial Glycemic Excursions and Hypoglycemia
Subgroup: Bolus Dose Given
Within 15 Minutes Before Meals
Analog Alone
(N=103)
Hylenex
Pretreatment
(N=184)
Secondary Objectives
• Compare patient-reported outcomes measures (Diabetes Treatment
Satisfaction, Quality of Life and Device Handling Issues) using Hylenex
recombinant pretreatment versus standard CSII without pretreatment
• Gather data for pre-specified subgroup analyses
• Evaluate safety and efficacy of treatment during 18 months extension
phase (study is ongoing, data not yet available)
Study Schema
Baseline
7.69
Endpoint
Change
7.56
Baseline
-0.14
Endpoint
7.70
7.52
Number
of events
% of
all
event
s
Rate/
month
16,435
8.4
12.1
Inclusion/Exclusion Criteria
Generally Healthy Males and females with type 1 diabetes >12 months
18 years and older
Current use of CSII, <300 U/insulin/day
BMI 18-45 kg/m2
A1C 6.5-9.5%
Fasting C-peptide <0.6 ng/mL
Study Procedures
• Randomize subjects to receive either Standard CSII or Hylenex
Pretreatment (1.0 mL Hylenex recombinant infused through CSII
infusion cannula immediately following infusion site placement every 3
days)
• At randomization, all subjects reduce bolus doses by ~15% and retitrate
to target value <140 mg/dL 90 min after meals
• Routine CGM users allowed to use CGM (unblinded) throughout study
• CHO counting encouraged, not required
• SMBG mandated before meals, at bedtime and 90 minutes after at least
2 meals each day + 3:00 AM testing 1/week
• ALL SMBG records uploaded directly from cellular-capable meter to
central server
• Insulin dose, dose timing, meal data and SMBG data analyzed by
“smart” algorithm to feedback dosing recommendations to investigators
• Study visits: screen, randomization, 2w, 1mo, 2mo, 3mo, 4mo and 6mo
Subject Characteristics
(All Subjects with T1DM)
Hylenex Pretreatment
(n=342)
Standard CSII
(n=113)
46.9 (13.0)
49.7(14.7)
% Male
48.8
43.4
% Caucasian
95.9
94.7
% CGM routine users
26.3
24.8
Years since diagnosis (SD)
26.7 (12.8)
28.9 (13.8)
% with hypo unawareness
9.9
11.5
10.1 (5.7)
11.4 (7.0)
Aspart users
47.7
48.7
Lispro users
42.4
41.6
Glulisine users
9.6
9.7
Mean baseline BMI (SD)
28.6 (5.0)
28.4 (5.0)
Screening A1C (SD)
7.79 (0.76)
7.78 (0.74)
Mean age (SD)
Years of regular pump use (SD)
Difference (CI)
-0.18
0.05
(-0.08, 0.18)
Hypoglycemia Results (drawn from automatic meter
uploads of >261,000 individual records)
Hylenex Pretreatment
(N=298)
•
•
•
•
•
•
Change
≤70 mg/dL
Analog Alone
(N=103)
Number of
events
% of
all
even
ts
Rate/
month
Rate
Ratio
p-value
6,292
9.7
13.8
.88
.08
<56 mg/dL
4,210
2.1
3.1
1,824
2.8
4.0
.77
.02
Nocturnal
2,302
1.2
1.7
966
1.5
2.1
.79
.02
Severe
9
<<1
0.0061
8
<<1
0.0157
.39
.08
(9 subjects)
(6 subjects)
Subgroup: Bolus Dose
Given Within 15 Minutes After Meals
Hylenex
Pretreatment
(N=90)
Analog Alone
(N=63)
Analog Alone
(N=28)
Rate/ month
Rate/ month
Rate
Ratio
p-value
Rate/ month
Rate/ month
Rate
Ratio
p-value
≤70 mg/dL
11.6
14.7
.79
.013
12.5
13.1
.95
.73
<56 mg/dL
2.9
4.2
.69
.011
3.4
4.2
.80
.26
Nocturnal
1.6
2.1
.78
.051
1.7
2.4
.70
.056
Severe
0.0055
0.0160
.34
.12
0.0090
0.0072
1.25
.84
•Timing of Bolus Dose determines type of metabolic response:
• Mean dose timing within 15 minutes before meals results
in exaggerated hypoglycemia benefit (above) without any
post-meal glucose excursion benefit (below)
• Mean dose timing within 15 minutes after meals results in
diminished hypoglycemia benefit (above) with trend for improved
35
post-meal glucose excursion (below)
30
Overall Glycemic Excursions (mg/dL)
Abstract
of Washington, Seattle, WA, 2Alanta Diabetes Associates, Atlanta, GA, 3University of Miami, Miami, FL, 4University of Colorado, Denver, CO, 5University of North Carolina, Chapel Hill, NC, 6Halozyme Therapeutics Inc, San Diego, CA.
No difference in excursion with
p-value for difference = 0.94
25
20
Excursion reduced
by 40% with p-value for
difference = 0.11
Hylenex Pretreatment
Standard CSII
15
10
Bolus Dose Given Within 15 Minutes Before Meals
Change
Baseline
Hylenex Pretreatment
(n=127)
Lispro
7.61
7.47
-0.14
7.74
7.61
-0.13
7.57
7.87
7.71
-0.16
Difference (CI)
Bolus Dose Given Within 15 Minutes After Meals
7.41
-0.16
0.03
(-0.17, 0.23)
.78
7.82
7.61
-0.21
0.08
(-0.13, 0.27)
.38
Glulisine Alone
(n=10)
7.73
7.59
-0.14
-0.02
(-0.43, 0.40)
No Difference in Total Daily Dosage of Insulin
Mean
Doses
Hylenex Pretreatment
(N=342)
Analog Alone
(N=114)
1280
320
320
80
80
20
20
5
5
0
1
2
3
Month
4
5
6
0
1
2
3
Month
4
5
6
• Anti-rHuPH20 and anti-insulin antibodies were determined at every visit
• 51 of 455 subjects (shown above) were positive at any time during study:
• 36 of 342 (10.5%) Hylenex-treated subjects
• 15 of 113 (13.3%) control subjects
• All but two subjects showed titers that fluctuated within ±1 dilution of baseline
value, indicating no measurable change over time
• Two subjects in the Hylenex pretreatment group showed more than one
dilution increase in titer over time (shown in heavy lines above, subjects 030004 and 027-004); no adverse events were correlated with these responses
• Anti-insulin and anti-analog-specific antibodies were common and were not
affected by Hylenex treatment (data not shown)
Other Results
• >98% of subjects reported that the infusion site change process
was either “very easy” or “easy” for both treatment groups
• Mean additional time required for infusion set change for Hylenex
Pretreatment users was 3.0 (SD=2.8) minutes
• With the exception of infusion site related adverse events (see table below), adverse
events were balanced across treatment groups
• 7 subjects on Hylenex pretreatment discontinued because of adverse events; 2 of these
were judged related (itching and pain at infusion site) or possibly related (keratoderma
and urticaria) to study drug
• 11 subjects (3.2%) on Hylenex pretreatment and 8 subjects (7.1%) on standard CSII had
serious adverse events; 1 subject had serious adverse events (hypoglycemia and
seizure) judged possibly related to Hylenex study drug
• 1 subject died (arteriosclerosis) during Hylenex treatment
• Infusion site pain (typically mild discomfort) is more common with Hylenex pretreatment
• Hylenex pretreatment used in the CSII treatment setting in T1DM results in
noninferior A1C outcome with improvement in measures of hypoglycemia
• Hylenex pretreatment has a preferentially beneficial effect on hypoglycemia
parameters when Bolus Doses are delivered before meals
• Hylenex pretreatment shows a trend for preferential beneficial effect on
postprandial glycemic excursions when Bolus Doses are delivered after meals
• Hylenex pretreatment is well tolerated and no safety signal is identified beyond
mild infusion site discomfort (rarely leading to discontinuation of treatment)
• Extensive immunogenicity testing shows no evidence of a safety signal for
Hylenex in this population, and also no effect on anti-insulin antibody formation
• Hylenex pretreatment was easy to use and added little time to infusion set
change process
Hylenex Pretreatment
Standard CSII
n (%)
n (%)
Any General Disorder or Administration
Site Condition
68 (19.9%)
9 (8.0%)
Pain , discomfort or paresthesia
53 (15.5%)
7 (6.2%)
Hematoma, bruising or hemorrhage
13 (3.8%)
0
Erythema
5 (1.5%)
1 (0.9%)
Edema
2 (0.6%)
1 (0.9%)
Induration
3 (0.9%)
0
N=342
N=113
Dose (U)
SD
Range
Dose (U)
SD
Range
Treatment
Difference
Daily Bolus
21.7
13.0
4-83
23.2
17.5
6-108
-1.5
.31
Pruritis
5 (1.5%)
0
Daily Basal
28.1
13.2
7-91
24.7
13.6
7-82
2.2
.12
Feeling hot or warmth
2 (0.6%)
0
Total Daily
49.8
22.7
17-168
48.1
28.0
17-181
0.9
.73
Rash or scar
3 (0.9%)
0
p-value
1280
Summary
Event Term(s)
.94
5120
Hylenex Pretreatment Safety Summary
p-value
Aspart Alone
(n=48)
Hylenex Pretreatment
(n=28)
Glulisine
Change
Lispro Alone
(n=45)
Hylenex Pretreatment
(n=141)
Aspart
Endpoint
5120
• Hylenex Pretreatment subjects showed 0.23 kg less weight gain
than the standard CSII group during study (p=.48)
No Differences in A1C Outcomes by Analog Used
Endpoint
Anti-rHuPH20 titers over time are shown below for all subjects who tested
positive at any time after screening
5
0
Baseline
rHuPH20 Immunogenicity Results
Titer
1University
Conclusions
• Hylenex pretreatment was well tolerated
• Pretreatment of CSII infusion sites with Hylenex at the time of each
infusion set change results in improved rates of hypoglycemia while
achieving noninferior A1C control, validating the utility of the “FastIn, Fast-Out” profile of ultrafast insulin
• Bolus dose timing was shown to impact the metabolic impact of
Hylenex pretreatment and informs hypotheses for further testing
References
1. Elleri D, et al. BMC Medicine. 2011;9:120-129.
2. Hylenex [package insert]. San Diego, CA: Halozyme Therapeutics
3. Vaughn DE, Muchmore DB. Endocr Pract. 2011;17:914-921.
4. Morrow L, et al. Diabetes Care. 2012;36(2):273-275.
5. Hompesch M, et al. Diabetes Tech. Ther. 2012;14:218-224
Contact:
Douglas B. Muchmore, MD
Halozyme Therapeutics
13888 Sorrento Valley Road
San Diego, CA 92121 USA
+1 858 702 8289

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